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Cardiovascular toxicology is concerned with the adverse effects of extrinsic and intrinsic stresses on the heart and vascular system. Extrinsic stress involves exposure to therapeutic drugs, natural products, and environmental toxicants. Notably, the heart and vessels are somewhat protected from xenobiotics due to classical defense and detoxification organs (e.g., skin, lungs, and liver), thus many extrinsic cardiotoxins are intentionally administered substances. Intrinsic stress refers to exposure to toxic metabolites derived from nontoxic compounds such as those found in food additives and supplements. The intrinsic exposures also include secondary neurohormonal disturbance such as overproduction of inflammatory cytokines derived from pressure overload of the heart and counter-regulatory responses to hypertension or uremic toxins that arise from renal failure. These toxic exposures result in alterations in biochemical pathways, defects in cellular structure and function, and pathogenesis of the affected cardiovascular system. The manifestations of toxicological response of the heart include cardiac arrhythmia, hypertrophy, and overt heart failure. The responses of the vascular system include changes in blood pressure and lesions in blood vessels in the form of atherosclerosis, hemorrhage, and edema.
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This chapter is divided into two parts, separately focusing on the heart and the vascular systems. For a better understanding of the toxic manifestations of the cardiovascular system, an overview of the physiology and biochemistry of the heart and the vascular system is presented in relation to toxicological concerns. The toxicological responses of the heart and the vascular system and the mechanisms underlying these responses are the major focus of this chapter. This chapter also presents a brief discussion of chemicals that affect the heart and the vascular system.
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OVERVIEW OF THE HEART
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Overview of Cardiac Structural and Physiological Features
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Cardiac muscle, along with nerve, skeletal muscle, and smooth muscle, is one of the excitable tissues of the body. It shares many bioelectrical properties with other excitable tissues, and also has unique features associated with cardiac structural and physiological specificities. Fig. 18-1 illustrates the basic anatomy of the heart. With regard to cardiac toxicology, this section will only review some features of cardiac physiology and structures. There are many textbooks of cardiac anatomy and physiology that provide extensive knowledge basis of cardiac physiology and structural properties, which will not be repeated in this section.
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Review of Cardiac Structure
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The primary contractile unit within the heart is the cardiac muscle cell, or cardiac myocyte. Cardiac myocytes are composed of several major structural features and organelles, as illustrated in Fig. 18-2. A primary component is the contractile element known as the myofibril. Each myofibril consists of a number of smaller filaments (the thick and thin myofilaments). The thick filaments are special assemblies of the protein myosin, ...